Biomedical subjects

B Szabo

Publications and source records attributed to B Szabo.

At least 37 records · Page 2Linked to original sources

PubMed1998

Inhibition of GABAergic inhibitory postsynaptic currents by cannabinoids in rat corpus striatum.

Electrophysiological consequences of activation of cannabinoid receptors have been mostly investigated on neuronal cell lines and on cells transfected with cannabinoid receptors. The aim of the present experiments was to study cannabinoid effects on identified neurons in situ. Electrically-evoked postsynaptic currents and voltage-dependent calcium currents were investigated in the principal neurons of the corpus striatum, the medium spiny neurons, with the patch-clamp method for brain slices. These neurons were chosen because they produce messenger RNA for cannabinoid receptors and because the density of cannabinoid binding sites in the striatum is high. Activation of muscarinic receptors by carbachol (10(-5) M) reduced inhibitory postsynaptic current amplitude by 67%. The synthetic cannabinoid receptor agonist R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4- benzoxazin-yl]-(1-naphtalenyl)methanone (WIN55212-2; 10(-8) to 10(-5) M) dose-dependently reduced striatal inhibitory postsynaptic currents; the maximum effect, inhibition by 52%, was observed at 10(-6) M. Another cannabinoid agonist, (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydr oxypropyl)cyclohexanol (CP55940; 10(-6) M), also reduced inhibitory postsynaptic currents, by 50%. The CB1 cannnabinoid receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)4-methyl-3-pyra zolecarboxamide (SR141716A; 10(-6) M) had no effect when given alone but abolished the effect of WIN55212-2 (10(-6) M). WIN55212-2 (10(-6) M) did not change the current evoked by the GABA(A)-receptor agonist muscimol (10(-6) M). Activation of muscarinic receptors by carbachol (10(-5) M) inhibited voltage-dependent calcium currents by 21%, but the cannabinoid receptor agonist WIN55212-2 (10(-6) M) was without effect. The results show that activation of CB1 cannabinoid receptors reduces GABAergic inhibitory postsynaptic currents in medium spiny neurons of the corpus striatum: the likely mechanism is presynaptic inhibition of GABA release from terminals of recurrent axons of the medium spiny neurons themselves.

Animals↗

PubMed1998

[Exophthalmos in giant cerebral arteriovenous vascular malformations].

We present the most important ophthalmologic signs related to the angiocinematographic aspects in two patients presenting giant arteriovenous malformations in the frontal part of the brain. In both cases the first clinical sign of the disease was unilateral proptosis associated with scleroconjunctival arteriovenous malformation. In the presented cases we could not establish any relationship between the intensity of the proptosis, the scleroconjunctival vascular malformation and the size of the intracranial arteriovenous malformation. We point on the importance of the proptosis associated with scleoconjunctival vascular malformation representing the first signs in intracranial arteriovenous malformations.

Adult↗

PubMed1998

Ovariectomy and estrogen-induced alterations in myocardial contractility in female rabbits: role of the L-type calcium channel.

The effects of ovariectomy and estrogen replacement on myocardial contractility were examined in female rabbits. Ovariectomy failed to alter left ventricular mass, papillary muscle cross-sectional area or isometric force. Estrogen replacement after ovariectomy (0.15 microg/kg/day i.m. 17beta-estradiol acetate for 7 days) increased left ventricular mass and papillary muscle mass, and reduced isometric force compared to control and ovariectomy groups. Ovariectomy did not alter increased isometric force with isoproterenol, but decreased the ED50 for Bay K8644 (compared to control and estrogen groups). Estrogen replacement increased the ED50 for isoproterenol- and Bay K8644-induced isometric force compared to control and ovariectomy groups. Ovariectomy increased and estrogen replacement decreased isometric force associated with increased Ca++o. Acute exposure to 17beta-estradiol or diethylstilbesterol (10(-7) M, 10(-6) M) failed to alter isometric force in control papillary muscles. Estrogen replacement reduced the number, but not the dissociation constant for 3H-nitrendipine binding in plasma membrane preparations (compared to ovariectomy and control groups). Peak L-type calcium currents in isolated ventricular myocytes from the three treatment groups were not significantly different. The data are consistent with an ovariectomy-induced increase and estrogen-induced decrease in L-type calcium channel density in rabbit myocardium. Estrogen-induced alterations in L-type calcium channel expression and contractility are subsequently modified by estrogen-induced cardiac hypertrophy.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1997

Subtype determination of soma-dendritic alpha2-autoreceptors in slices of rat locus coeruleus.

The aim of the study was to subclassify the soma-dendritic alpha2-autoreceptors in the locus coeruleus (LC) of the rat by means of antagonists. To this end, the frequency of spontaneous action potentials was recorded extracellularly from single LC neurones in brain slices. The neurones fired spontaneously at an average rate of 1 Hz. The selective alpha2-adrenoceptor agonist 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) and noradrenaline decreased the action potential discharge with IC50 values of 5 and 510 nM, respectively. The concentration-inhibition curves of UK 14,304 and noradrenaline were shifted to the right by phentolamine (0.15 microM) and rauwolscine (0.15 microM) but not by prazosin (1 microM). Apparent Kd values of phentolamine were 17 nM (against UK 14,304) and 20 nM (against noradrenaline). Apparent Kd values of rauwolscine were 47 nM (against UK 14,304) and 70 nM (against noradrenaline). (+)-Oxaprotiline (1 microM) suppressed the firing of the neurones within 10 to 33 min. In the continued presence of oxaprotiline, phentolamine and rauwolscine restored firing with EC50 values of 120 and 250 nM, respectively. Prazosin (1 microM) again was ineffective. All three antagonist affinity estimates - against UK 14,304, exogenous noradrenaline and endogenous noradrenaline (that accumulates in the extracellular space in the presence of oxaprotiline) - yield an affinity order phentolamine > rauwolscine >> prazosin, prazosin being ineffective even at a concentration of 1 microM. These findings identify the soma-dendritic alpha2-autoreceptors of the LC as the rat variant of the alpha2A/D-adrenoceptor, i.e. alpha2D. Not only presynaptic but also soma-dendritic alpha2-autoreceptors may at least predominantly be alpha2A/D throughout the nervous system.

Action Potentials↗

PubMed1997

Similarities between early and delayed afterdepolarizations induced by isoproterenol in canine ventricular myocytes.

OBJECTIVES: This study aims at clarifying the role of cellular Ca2+ overload and spontaneous sarcoplasmic reticulum (SR) Ca2+ release in the generation of early afterdepolarizations (EAD) by isoproterenol. The involvement of a Ca(2+)-activated membrane current in isoproterenol-induced EAD is investigated. METHODS: Membrane potential and contraction (an indicator of SR Ca2+ release) were recorded in canine left ventricular myocytes at pacing cycle lengths (CL) of 300-4000 ms. Threshold concentration for EAD was 20-50 mmol/l isoproterenol. Ni2+ (2.0-5.0 mmol/l) was used at normal and high (5.4 mmol/l) [Ca2+]o to examine the role of Ca2+ current and/or Na(+)-Ca2+ exchange (1Na-Ca) in EAD. RESULTS: In all cells delayed afterdepolarizations (DAD) appeared during isoproterenol. In most (approximately equal to 70%) cells EAD were also generated, which were fast-pacing dependent, occurring only at CL of 400-1000 ms. EAD were always initiated by a delay in repolarization. Early aftercontractions preceded the EAD upstrokes, often occurring without them. They coincided with the initial delays in repolarization. During treatment with isoproterenol, Ni2+ and high [Ca2+]o, EAD and DAD were suppressed despite the continued presence of early and delayed aftercontractions. CONCLUSIONS: Our data indicate that beta-adrenergic EAD share a common ionic mechanism with DAD in terms of cellular Ca2+ overload and spontaneous SR Ca2+ release. beta-Adrenergic EAD consist of two phases: (1) a conditional phase coinciding with the onset of an early aftercontraction, often followed by (2) an EAD upstroke. A Ca2(+)-activated membrane current, probably I Na-Ca, is necessary at least for the initiation of these EAD.

Action Potentials↗

PubMed1997

Facilitation of epinephrine-induced afterdepolarizations by class III antiarrhythmic drugs.

The electrophysiologic actions of epinephrine (10(-9) M, 10(-8) M, and 10(-7) M) were evaluated in canine Purkinje fibers pretreated with the class III antiarrhythmic drugs clofilium (10(-7) M) or d,l-sotalol (10(-6) M). Clofilium and d,l-sotalol prolonged action potential duration at 50% and 90% of repolarization without provoking early afterdepolarization (EAD) or delayed afterdepolarization (DAD). Subsequent administration of epinephrine provoked both bradycardia-dependent EADs and tachycardia-dependent DADs in clofilium-treated Purkinje fibers, with predominantly EADs observed in d,l-sotalol-treated Purkinje fibers. A temporary increase in Ca0(+2) from 1.35 mM to 5 mM suppressed both EADs and DADs. The data demonstrate facilitation of epinephrine-induced EADs and DADs by class III antiarrhythmic drugs. The acute suppression of both EADs and DADs observed following an acute increase in Ca0(+2) suggests inward Na(+)-Ca0(+2) exchange current as a basis for both EADs and DADs observed in the presence of class III antiarrhythmic drugs and epinephrine.

Action Potentials↗

PubMed1997

Role of I1 imidazoline receptors in the sympathoinhibition produced by intracisternally administered rilmenidine and moxonidine.

The role of alpha 2-adrenoceptors and I1 imidazoline receptors in the cardiovascular effects of rilmenidine (CAS 54187-04-1), moxonidine (CAS 75438-57-2) and guanabenz (CAS 23256-50-0) was studied in conscious rabbits. In radioligand binding studies, rilmenidine and moxonidine are selective for I1 imidazoline receptors (vs. alpha 2-adrenoceptors) and guanabenz is selective for alpha 2-adrenoceptors (vs. I1 imidazoline receptors). Efaroxan (CAS 89197-00-2; selective for I1 imidazoline receptors) and yohimbine (CAS 65-19-0; selective for alpha 2-adrenoceptors) were used as antagonists. All drugs were injected into the cisterna magna. Guanabenz (1, 3, 10 and 30 micrograms kg-1), rilmenidine (1, 3, 10 and 30 micrograms kg-1) and moxonidine (0.03, 0.1, 0.3 and 1 microgram kg-1) dose-dependently lowered blood pressure, heart rate and the plasma concentration of noradrenaline. In the antagonism experiments, guanabenz (10 micrograms kg-1), rilmenidine (10 micrograms kg-1) and moxonidine (0.3 micrograms kg-1) were administered first; they caused equal hypotension. Injection of the agonists was followed by injection of efaroxan (0.3-1 microgram kg-1) or yohimbine (0.1-0.3 micrograms kg-1). Efaroxan and yohimbine were equieffective at antagonizing the effects of guanabenz. In contrast, efaroxan was more effective than yohimbine at antagonizing the effects of rilmenidine and moxonidine. The results show that intracisternally administered guanabenz, rilmenidine and moxonidine cause sympathoinhibition. alpha 2-Adrenoceptors are responsible for the sympathoinhibition produced by guanabenz. In contrast, I1 imidazoline receptors are involved in the sympathoinhibition caused by rilmenidine and moxonidine.

Adrenergic alpha-2 Receptor Antagonists↗

PubMed1996

Failure of tyramine to release neuronal ATP as a cotransmitter of noradrenaline in the guinea-pig vas deferens.

Contractions, release of noradrenaline and release of ATP elicited by the indirectly acting sympathomimetic amine tyramine and responses elicited by exogenous noradrenaline were studied in the isolated vas deferens of the guinea pig. Release of noradrenaline was assessed as overflow of tritium after preincubation with [3H]-noradrenaline. ATP was measured by means of the luciferin-luciferase technique. In tissues pretreated with pargyline 1 mM, tyramine 300 microM, when added to the superfusion medium for 2 min, elicited contraction and an overflow of tritium (mainly [3H]-noradrenaline) and ATP. Contraction and ATP overflow responses were prevented and tritium overflow was greatly reduced by desipramine 10 microM. Prazosin 0.3 microM abolished contractions and evoked ATP overflow without changing tritium overflow. Blockade of postjunctional P2-purinoceptors by suramin 300 microM caused a marked decrease of tyramine-evoked contractions and a slight reduction of tritium overflow whereas evoked ATP overflow was markedly increased. The effect on contraction was not shared by two other P2-purinoceptor antagonists, namely pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) 32 microM and diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) 32 microM: PPADS increased contractions about fourfold, whilst DIDS had no effect at all. When the vas deferens was superfused for 24 min with medium containing tyramine 300 microM, evoked contractions and tritium overflow continued throughout whereas ATP overflow faded rapidly to basal values. In the presence of prazosin 0.3 microM, tyramine 300 microM again failed to elicit contractions as well as an overflow of ATP. Application of noradrenaline 10 microM instead of tyramine also resulted in prolonged contraction and an overflow of ATP that declined rapidly. It is concluded that all ATP released by tyramine is non-neuronal in origin, secondary to the activation of postjunctional alpha 1-adrenoceptors by released noradrenaline. The non-neural ATP does not seem to play a functional role in smooth muscle contraction and derives from a postjunctional source which is subject to a rapid depletion upon sustained alpha 1-adrenoceptor activation.

Adenosine Triphosphate↗

PubMed1996

No evidence for functional imidazoline receptors on locus coeruleus neurons.

alpha 2-Adrenoceptor agonists inhibit the firing of locus coeruleus (LC) neurons. It was recently observed that the alpha-adrenoceptor agonists clonidine, rilmenidine and cirazoline, when injected intravenously in anaesthetized rats pretreated with the irreversible alpha 2-adrenoceptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), excite the LC. The effect was attributed to activation of I1 imidazoline receptors. The aim of the present experiments was to characterize the direct effect of alpha 2-adrenoceptor and I1 imidazoline receptor agonists on LC neurons. Electrical activity of LC neurons was extracellularly recorded in midpontine slices prepared from the rat brain. Concentration-response curves were obtained for the alpha 2-agonist noradrenaline and the mixed I1/alpha 2-receptor agonists clonidine, rilmenidine and moxonidine in slices without treatment and in slices treated with 6-chloro-N-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SK&F86466) or EEDQ, alpha 2-adrenoceptor antagonists with low affinity for I1 and I2 imidazoline receptors, respectively. All four agonists concentration-dependently reduced the firing rate of the neurons, with full inhibition at higher concentrations. SK&F86466 shifted the concentration-response curves of the agonists to the right; the calculated antagonist dissociation constants are compatible with an effect of the agonists on alpha 2-adrenoceptors. EEDQ completely prevented the inhibition by the agonists. Neither in SK&F86466- nor in EEDQ-treated slices was an excitation by clonidine, rilmenidine and moxonidine observed. We conclude that the LC neurons do not possess functional I1 (and also no I2) imidazoline receptors. The effects of noradrenaline, clonidine, rilmenidine and moxonidine on the neurons can be fully explained with an interaction with inhibitory alpha 2-adrenoceptors (probably of the alpha 2D subtype). The excitation of the LC by imidazoline receptor agonists under in vivo conditions, hence, is not a direct effect on the neurons of the LC.

Adrenergic alpha-Agonists↗

PubMed1995

Downregulation of muscarinic- and 5-HT1B-mediated modulation of [3H]acetylcholine release in hippocampal slices of rats with fimbria-fornix lesions and intrahippocampal grafts of septal origin.

Adult Long-Evans female rats sustained electrolytic fimbria-fornix lesions and, two weeks later, received intrahippocampal suspension grafts of fetal septal tissue. Sham-operated and lesion-only rats served as controls. Between 6.5 and 8 months after grafting, both the [3H]choline accumulation and the electrically evoked [3H]acetylcholine ([3H]ACh) release were assessed in hippocampal slices. The release of [3H]ACh was measured in presence of atropine (muscarinic antagonist, 1 microM), physostigmine (acetylcholinesterase inhibitor, 0.1 microM), oxotremorine (muscarinic agonist, 0.01 microM-10 microM), mecamylamine (nicotinic antagonist, 10 microM), methiothepin (mixed 5-HT1/5-HT2 antagonist, 10 microM), 8-OH-DPAT (5-HT1A agonist, 1 microM), 2-methyl-serotonin (5-HT3 agonist, 1 microM) and CP 93129 (5-HT1B agonist, 0.1 microM-100 microM), or without any drug application as a control. In lesion-only rats, the specific accumulation of [3H]choline was reduced to 46% of normal and the release of [3H]ACh to 32% (nCi) and 43% (% of tissue tritium content). In the grafted rats, these parameters were significantly increased to 63%, 98% and 116% of control, respectively. Physostigmine reduced the evoked [3H]ACh release and was significantly more effective in grafted (-70%) than in sham-operated (-56%) or lesion-only (-54%) rats. When physostigmine was superfused throughout, mecamylamine had no effect. Conversely, atropine induced a significant increase of [3H]ACh release in all groups, but this increase was significantly larger in sham-operated rats (+209%) than in the other groups (lesioned: +80%; grafted: +117%). Oxotremorine dose-dependently decreased the [3H]ACh release, but in lesion-only rats, this effect was significantly lower than in sham-operated rats. Whatever group was considered, 8-OH-DPAT, methiothepin and 2-methyl-serotonin failed to induce any significant effect on [3H]ACh release. In contrast, CP 93129 dose-dependently decreased [3H]ACh release. This effect was significantly weaker in grafted rats than in the rats of the two other groups. Our data confirm that cholinergic terminals in the intact hippocampus possess inhibitory muscarinic autoreceptors and serotonin heteroreceptors of the 5-HT1B subtype. They also show that both types of receptors are still operative in the cholinergic terminals which survived the lesions and in the grafted cholinergic neurons. However, the muscarinic receptors in both lesioned and grafted rats, as well as the 5-HT1B receptors in grafted rats show a sensitivity which seems to be downregulated in comparison to that found in sham-operated rats. In the grafted rats, both types of downregulations might contribute to (or reflect) an increased cholinergic function that results from a reduction of the inhibitory tonus which ACh and serotonin exert at the level of the cholinergic terminal.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1995

Involvement of peripheral presynaptic inhibition in the reduction of sympathetic tone by moxonidine, rilmenidine and UK 14304.

We studied the possibility that presynaptic inhibition of transmitter release from postganglionic sympathetic neurons contributes to the overall reduction of sympathetic tone produced by moxonidine, rilmenidine and 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline tartrate (UK 14304). In pithed rabbits without electric stimulation, moxonidine, rilmenidine and UK 14304 caused a long-lasting, > 10 min, increase in arterial pressure. Heart rate was not changed. In pithed rabbits in which sympathetic tone was created by electric stimulation through the pithing rod (2 Hz), the same doses of moxonidine, rilmenidine and UK 14304 caused only a brief, < 10 min, blood pressure rise. Heart rate was decreased, as were the plasma concentrations of noradrenaline and adrenaline. Dose-response curves for the effects on the plasma noradrenaline concentration (stimulated pithed rabbits) were compared with previously obtained dose-response curves for depression of renal sympathetic nerve activity (conscious rabbits). For each drug, the curve describing peripheral presynaptic inhibition and the curve describing central sympathoinhibition were very similar. Both the power and the dose dependence of the peripheral inhibitory effect support its contribution to the overall decrease in sympathetic tone produced by clonidine-like drugs in intact animals. The peripheral effect in all likelihood consists in activation of presynaptic alpha 2-autoreceptors. The agreement of the dose-response curves for the peripheral and for the central effect supports the view that the central effect, like the peripheral one, is mediated through alpha 2-adrenoceptors.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1995

Involvement of alpha 2-adrenoceptors in the cardiovascular effects of moxonidine.

The central sympathoinhibition caused by moxonidine has been explained by activation of alpha 2-adrenoceptors on the one hand, and by an action at imidazoline I1 receptors on the other hand. In order to examine these possibilities, effects of moxonidine were compared with those of 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14304), an alpha 2-adrenoceptor agonist with very low affinity for I1 receptors, in conscious rabbits. The interaction with yohimbine, an alpha 2-adrenoceptor antagonist with very low affinity for imidazoline I1 receptors, was also studied. Moxonidine 3-100 micrograms kg-1 and UK 14304 1-30 micrograms kg-1 i.v. elicited similar effects: they decreased arterial blood pressure after a transient increase, decreased renal sympathetic nerve activity (recorded with chronically implanted electrodes), decreased heart rate and decreased the plasma noradrenaline concentration. Yohimbine given i.v. antagonized the effects of moxonidine and of UK 14304 in a similar manner. Yohimbine injected into the cisterna magna (i.c.) prevented the hypotension but did not change the decrease in plasma noradrenaline and heart rate, again in the case of both moxonidine and UK 14304. The agreement of the effect patterns of moxonidine and UK 14304, and the similar antagonism of yohimbine against either drug, demonstrate involvement of alpha 2-adrenoceptors in their central sympathoinhibitory action. The resistance of the bradycardia and the plasma noradrenaline fall against yohimbine i.c. indicates a contribution of presynaptic alpha 2-adrenergic inhibition of transmitter release from postganglionic sympathetic neurons to the overall reduction of sympathetic tone.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1995

Mechanism of sympathoinhibition by imidazolines.

The aim of the present study is to characterize the cardiovascular effects of rilmenidine and moxonidine, two recently developed centrally acting antihypertensive drugs. Rilmenidine and moxonidine are alpha 2-adrenoceptor agonists and, in addition, possess affinity for imidazoline (I1)-receptors. To determine if alpha 2- or I1-receptors are involved in sympathoinhibition, rilmenidine and moxonidine were compared with UK 14304, an alpha 2-agonist devoid of affinity for I1-receptors, and antagonism by the "pure" alpha 2-adrenoceptor antagonists yohimbine, SK&F86466, and RX821002 was studied. When injected intravenously into conscious rabbits, rilmenidine and moxonidine, on the one hand, and UK 14304, on the other, elicited a similar pattern of effects. Thus, transient hypertension was followed by long-lasting hypotension accompanied by a decrease in heart rate, renal sympathetic nerve firing rate, and plasma norepinephrine concentration. The effects of rilmenidine, moxonidine, and UK 14304 were antagonized by intravenously administered yohimbine, SK&F86466, and RX821002. The effects of moxonidine and UK 14304 were also prevented by yohimbine injected into the cisterna magna. Altogether, the degree of antagonism of the effects of rilmenidine and moxonidine did not differ from the degree of antagonism of the effects of UK 14304. Rilmenidine, moxonidine, and UK 14304 were also given to pithed rabbits in which a constant sympathetic tone was maintained by electrical stimulation of the sympathetic nerves. At doses that caused sympathoinhibition in conscious rabbits, they lowered the plasma norepinephrine concentration markedly. Our experiments show by direct measurement of sympathetic nerve activity and plasma norepepinephrine concentration that rilmenidine, moxonidine, and UK 14304 cause sympathoinhibition. As a consequence, blood pressure and heart rate decrease. The simplest interpretation of the blockade of central sympathoinhibition by the selective alpha 2-adrenoceptor antagonists is that rilmenidine, moxonidine, and UK 14304 primarily activated alpha 2-adrenoceptors. The decrease in plasma norepinephrine in pithed rabbits indicates peripheral presynaptic alpha 2-adrenoceptor-mediated inhibition of norepinephrine release per action potential from postganglionic sympathetic axons and suggests a contribution of this mechanism to the overall reduction in sympathetic tone.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1995

Cardiovascular effects of agmatine, a "clonidine-displacing substance", in conscious rabbits.

Agmatine has been identified as a "clonidine-displacing substance" in extracts from bovine brain. We studied its effect on cardiovascular regulation and the role played in this effect by alpha 2-adrenoceptors. In conscious rabbits, agmatine 10 micrograms kg-1 injected intracisternally (i.c.) caused no change, whereas agmatine 30, 100 and 300 micrograms kg-1 i.c. increased renal sympathetic nerve firing, the plasma concentration of noradrenaline and adrenaline and arterial blood pressure. Heart rate tended to be decreased. Yohimbine 1.5 micrograms kg-1 i.c. caused no change, whereas yohimbine 5, 15 and 50 micrograms kg-1 increased renal sympathetic nerve activity, the plasma concentration of noradrenaline and adrenaline, blood pressure and heart rate. In rabbit brain cortex slices preincubated with [3H]-noradrenaline, agmatine 1 to 100 microM did not modify the electrically evoked overflow of tritium (either 4 pulses at 100 Hz or 36 pulses at 3 Hz). The evoked overflow was reduced by 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14304) 0.03 to 30 nM (4 pulses at 100 Hz), and this inhibition was not affected by agmatine 10 and 100 microM. Agmatine did not change the basal efflux of tritium. The results show that agmatine, like yohimbine, causes central sympathoexcitation when given i.c., but agmatine differs from yohimbine in that it does not increase heart rate. Agmatine acts neither as an agonist nor as an antagonist at the alpha 2-autoreceptors in rabbit brain cortex. alpha 2-Adrenoceptors, therefore, are probably not involved in its cardiovascular effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1995

Role of calcium loading in early afterdepolarizations generated by Cs+ in canine and guinea pig Purkinje fibers.

INTRODUCTION: Our previous observations indicate that the Na+:Ca2+ exchange current (INa:Ca) plays an important role in early afterdepolarizations occurring at more negative Vm (L-EAD). The purpose of these studies was to examine the role of Ca(2+)-loading, which stimulates INa:Ca, in generation of L-EAD. METHODS AND RESULTS: Purkinje strands and preparations of ventricular myocardium from dogs and guinea pigs were superfused with oxygenated physiologic buffer solutions at 37 degrees C. To induce EADs, [K+]o was reduced to 2.0 to 3.0 mM and [Cs+]o (3.6 to 4.0 mM) was added at slow rates of < or = 0.3 Hz. Isometric contraction in canine Purkinje strands and guinea pig papillary muscles doubled in 1-hour exposure to Cs+ and low [K+]o at slow rates and the uptake of 45Ca2+ was approximately doubled after 30 minutes. Forty-three percent of Purkinje fibers developed L-EAD after a latent period of 17 to 123 minutes of exposure. Ouabain (0.2 microM) suppressed L-EAD within 10 minutes reversibly. Ca(2+)-loading (low [Na+]o or high [Ca2+]o) for 5 to 10 minutes before exposure to Cs+, low [K+]o, and slow rates resulted in rapid development of L-EAD in all preparations during subsequent exposure. In Ca(2+)-loaded preparations, delayed afterdepolarizations (DADs) as well as L-EADs developed. CONCLUSIONS: Reduction of K+ currents with Cs+, low [K+]o, and slow rates induced L-EAD in a fraction of Purkinje fibers after a latent period during which Ca(2+)-loading of the sarcoplasmic reticulum occurred, while fibers preloaded with Ca2+ developed L-EAD rapidly and uniformly. These findings indicate that Ca(2+)-loading is a critical condition for the development of L-EAD. Early suppression of L-EAD by ouabian suggests a dependence of L-EAD on low [Na+]i. These findings implicate INa:Ca in the generation of L-EAD.

Animals↗

PubMed1995

Involvement of monoamine uptake inhibition and local anesthesia in the cardiovascular response to cocaine in conscious rabbits.

The cardiovascular effect of cocaine in rabbits was examined for peripheral and central components and for the contribution of the primary actions of cocaine, i.e., inhibition of the high affinity uptake mechanisms for monoamines and local anesthesia. In pithed rabbits with electrically stimulated sympathetic outflow (2 Hz), cocaine (0.2-5 mg kg-1) lowered the clearance of [3H]norepinephrine from plasma and increased the plasma norepinephrine concentration. Cocaine (0.2 and 1 mg kg-1) increased blood pressure and heart rate, whereas after 5 mg kg-1 heart rate and blood pressure decreased briefly and then recovered. In conscious rabbits, cocaine (0.2 and 1 mg kg-1) reduced renal sympathetic nerve activity and tended to reduce blood pressure and heart rate. Cocaine (5 mg kg-1) increased sympathetic nerve activity, blood pressure and the plasma norepinephrine and epinephrine concentrations. The effects of the lower doses were abolished in animals pretreated with oxaprotiline, but were not changed in animals pretreated with fluvoxamine or SCH 23390 (R-(+)-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol) + sulpiride. The effects of cocaine (5 mg kg-1) were attenuated by SCH 23390 + sulpiride but were not changed after oxaprotiline or fluvoxamine. Procaine (15 mg kg-1) mimicked the effects of cocaine (5 mg kg-1) on blood pressure and renal sympathetic nerve activity. Blood pressure also was increased by lidocaine (6 mg kg-1). It is concluded that cocaine enhances peripheral sympathetic neuro-effector transmission. In conscious rabbits, however, low doses fail to raise blood pressure because they simultaneously depress central sympathetic tone by blockade of the uptake of norepinephrine in the central nervous system. High cocaine doses cause sympathoexcitation in conscious rabbits. The mechanism seems to be dual: blockade of dopamine uptake in the central nervous system and a (peripheral or central) local anesthetic action.

Anesthetics, Local↗

PubMed1994

Role of Na+:Ca2+ exchange current in Cs(+)-induced early afterdepolarizations in Purkinje fibers.

INTRODUCTION: The ionic mechanisms for early afterdepolarizations (EADs) have not been fully clarified. It has been suggested that L-type Ca2+ current (ICaL) is the primary current generating EADs that occur near the plateau level (E-EADs) of the membrane potential (Vm) when ICaL is enhanced. The purpose of these studies was to determine accurately the range of Vm at which EADs occur in Purkinje fibers with K+ currents blocked by Cs+ and to investigate the importance of Na+:Ca2+ exchange current (INa:Ca) as opposed to ICaL and other currents in the generation of EADs occurring later during repolarization (L-EADs). METHODS AND RESULTS: Shortened Purkinje strands from dogs and guinea pigs were superfused with physiologic solution containing Cs+ (3.6 mM) and a low [K+]o (3.0 or 2.0 mM) to induce EADs. The Vm of origin of EADs and their evolution were measured with the aid of phase plane plots of the rate of repolarization against Vm. L-EADs occurred over a wide range of Vm (-35 to -90 mV), generally more negative in guinea pig than in dog. Elevation of [Ca2+]o from 1.8 to 3.6 mM suppressed L-EADs within a few cycles, and they returned with continued exposure. After repeated exposures to high [Ca2+]o, L-EADs migrated toward less negative Vm when [Ca2+]o was reestablished to 1.8 mM in the presence of Cs+. Reduction of [Na+]o from 147.5 to 112.5 mM by substitution with Li+ or sucrose also rapidly depressed L-EADs. CONCLUSIONS: The observation of Cs(+)-induced L-EADs over a wide range of Vm indicates that there is not a single inward gated current as a common ionic mechanism for L-EADs but does not exclude an important role for INa:Ca, which can operate over a wide range of Vm. The rapid suppression of L-EADs with elevated [Ca2+]o and reduced [Na+]o and the migration of EADs to more positive Vm after exposures to high [Ca2+]o are compatible with INa:Ca as the major charge carrier for L-EADs.

Action Potentials↗

PubMed1994

Is the sympathoinhibitory effect of rilmenidine mediated by alpha-2 adrenoceptors or imidazoline receptors?

The involvement of alpha-2 adrenoceptors or imidazoline-1 receptors in the sympathoinhibitory effect of rilmenidine was investigated in conscious rabbits. Dose-response curves were determined for the effects of rilmenidine as well as of the alpha-2 selective agonist UK 14304 [5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline] on blood pressure, heart rate, renal postganglionic sympathetic nerve activity and the plasma norepinephrine concentration. The interaction with the alpha-2 selective antagonist SK&F 86466 [6-chloro-N-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine] also was studied. Rilmenidine (30-1000 micrograms kg-1 i.v.) and UK 14304 (1-30 micrograms kg-1 i.v.) elicited the same pattern of changes: transient hypertension followed by prolonged hypotension, bradycardia, a depression of sympathetic nerve firing and a fall in the plasma norepinephrine concentration. The ED50 values for these effects increased in the same order for both drugs: plasma norepinephrine fall < hypotension < depression of sympathetic nerve firing << bradycardia. Pretreatment with SK&F 86466 (3 mg kg-1 i.v. followed by an infusion of 1 mg kg-1 hr-1) altered the dose-response curves of rilmenidine and UK 14304 in a qualitatively and quantitatively almost identical manner; a rightward shift of the hypotensive, sympathoinhibitory and plasma norepinephrine level dose-response curves but no change of the dose-response curve for heart rate. The similarity of the effects of rilmenidine and UK 14304, and the almost identical antagonism of SK&F 86466 against either drug, argue against different sites of action of rilmenidine and UK 14304.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗